40,000 women die annually in the US as a result of breast cancer (BC). Although BC can be controlled if detected early, a significant number is not detected until later and these patients are treated using therapies to control both primary tumor and micro-metastatic disease. Therapy response is monitored using imaging and clinical assessment. Failure to detect early progression is a missed opportunity to adopt suitable therapies at a time when their impact on the disease can be maximized. Identification and validation of surrogate markers for identification of disease progression would provide clinicians with timely information in the management of BC therapy. The purpose of this application is to investigate the performance characteristics of the novel 88kDa autocrine growth factor GP88 as a surrogate marker for disease progression in breast cancer patients. GP88 is a critical biological driver for proliferation, survival, and invasiveness and is over expressed in invasive ductal cancers while negative in benign lesions and normal breast tissue. Two tests were developed to measure GP88 expression in cancer specimens;an IHC test for tumor biopsies and an EIA to measure circulating GP88 in biological fluids that have been validated in clinical trials. Tissue GP88 expression was predictive marker of BC recurrence while serum GP88 was elevated in BC patients with progressive disease, but not in BC patients with no evidence of disease. The specific aims of this revised SBIR Phase I are to investigate GP88 as a surrogate marker for disease progression in BC patients enrolled in the I-SPY Trial. The I-SPY trial is a national study to identify biomarkers predictive of response to therapy throughout the treatment cycle for women with Stage 3 breast cancer in neoadjuvant setting. This trial enrolled 221 patients with tissue and serum samples collected at specific time points pre and post-treatment and subjects followed for three years post-therapy. 122 (55%) patients benefited from neo-adjuvant treatment, 40 (18%) patients received some benefit (tumors reduced by 10% - 40%) and 59 (27%) patients showed no benefit (disease progressed). Aims are: 1: Determine if serum/tissue GP88 levels are a surrogate marker to identify breast cancer patients not benefiting from on-going neo-adjuvant chemotherapy. We will determine if there is a correlation between GP88 level and decreased/increased tumor volume in chemo-naive patients undergoing neo-adjuvant chemotherapy. 2: Determine if serum GP88 can be used to identify breast cancer patients most likely to have recurrence following an initial benefit from neo-adjuvant therapy. We will determine if there is a quantifiable difference in the risk of recurrence between those patients with high and low serum or tissue GP88 levels, prior to commencing neo-adjuvant therapy. Upon completion of these specific aims, this investigation will evaluate GP88 as a surrogate to identify disease progression in patients undergoing chemotherapy and additionally if initial serum GP88 level prior to commencing therapy is correlated to risk of recurrence and will provide additional tools to clinicians to monitor therapy response and disease progression during and after treatment. PUBLIC HEALTH RELEVANCE: (Lay) Breast cancer (BC) incidence in US women is second only to lung cancer and is one of the leading causes of cancer related death;40,000 women die annually. Patients in whom BC is detected as having spread beyond the breast are treated with radiation, chemotherapy and/or hormonal therapy prior to potential surgery. During and post treatment, tumor response is monitored using x-ray and clinical evaluation, imprecise methods for detection of subtle changes in tumor size that may indicate treatment failure. Use of X-ray imaging is relatively infrequent, subjective and requires availability of prior studies. There are no easily available specific diagnostic markers, direct or surrogate, for monitoring disease activity in BC. We have identified GP88 as a biomarker that may be used as a surrogate for detection of tumor changes in BC patients undergoing therapy. Preliminary data in a small study demonstrated that GP88 can be identified in serum of BC patients and is elevated in patients with progressive disease but not in patients with "no evidence of disease" following therapy, thus indicating that it may be useful as a surrogate marker for assessing response to chemotherapy. This project will investigate the use of GP88 as a surrogate marker for detection of non-response to chemotherapy and will provide information that may enable clinicians to adopt 2nd or 3rd line therapies when they may be most effective and may save patients un-necessary toxicity and costs associated with ineffective 1st line therapy.